Gastrointestinal disorders are common in elderly individuals. Research in the last decade has established that these age-related disorders are correlated with dramatic losses of neurons in the autonomic, or enteric, plexuses found in the wall of the digestive tract. Initial morphological observations have, however, focused primarily on establishing that the cell losses occur. Little information is available on the spatial patterning of the losses (e.g., is the large intestine affected more than the small intestine), the temporal patterning of the dissolution (e.g., when does cell death start and how does it progress), or the phenotypic specificity of the losses (e.g., which morphological and neurochemical phenotypes die). In addition, aging research has largely ignored the submucosal plexus in the stomach and intestines. Furthermore, such research has not examined age-related alterations in the extrinsic motor and sensory innervation linking the gut to the central nervous system. The present proposal's long term objective, which unifies its five specific aims, is to characterize the spatial, temporal and phenotypic patterns of neuronal aging in the gut, using immunohistochemical and anterograde tract tracing protocols. Aim 1: will determine whether the myenteric neuronal losses with aging are specific to particular neurochemical phenotypes. Aim 2: will examine spatial and temporal patterns of age-related morphological changes in the submucosal plexus. Aim 3: will explore whether loss of extrinsic vagal inputs to the gut precipitates enteric cell losses or, conversely, whether such extrinsic innervation is responsible for the prevention of cell losses in some regions. Aim 4: will examine the spatial and temporal patterns of change in the aging sympathetic nervous system motor and visceral afferent projections to the gastrointestinal tract. Aim 5: will assess age-associated remodeling of extrinsic neuronal endings throughout the GI tract. The overall goal of the project is to better understand the patterns of spatial, temporal and phenotypic changes in the neural innervation of the aging gastrointestinal tract. This information will provide a foundation needed for rational strategies for interventions or clinical management of some of the homeostatic and digestive disorders that affect appetite, ingestion, digestion, and motility, as well as ultimately nutrition and health, in the elderly.